Salmonella Typhimurium TTSS-2 deficient mig-14 mutant shows attenuation in immunocompromised mice and offers protection against wild-type Salmonella Typhimurium infection

Niladri Bhusan Pati,Bhaskar Saha,Mrutyunjay Suar,Vikalp Vishwakarma,Neera Singh,Sabyasachi Dash,Sathishkumar Selvaraj

doi:10.1186/1471-2180-13-236

Niladri Bhusan Pati, Bhaskar Saha + Show 5 more

Open Access

https://doi.org/10.1186/1471-2180-13-236

Copy DOI

Abstract

BackgroundDevelopment of Salmonella enterica serovar Typhimurium (S. Typhimurium) live attenuated vaccine carrier strain to prevent enteric infections has been a subject of intensive study. Several mutants of S. Typhimurium have been proposed as an effective live attenuated vaccine strain. Unfortunately, many such mutant strains failed to successfully complete the clinical trials as they were suboptimal in delivering effective safety and immunogenicity. However, it remained unclear, whether the existing live attenuated S. Typhimurium strains can further be attenuated with improved safety and immune efficacy or not.ResultsWe deleted a specific non-SPI (Salmonella Pathogenicity Island) encoded virulence factor mig-14 (an antimicrobial peptide resistant protein) in ssaV deficient S. Typhimurium strain. The ssaV is an important SPI-II gene involved in Salmonella replication in macrophages and its mutant strain is considered as a potential live attenuated strain. However, fatal systemic infection was previously reported in immunocompromised mice like Nos2−/− and Il-10−/− when infected with ssaV deficient S. Typhimurium. Here we reported that attenuation of S. Typhimurium ssaV mutant in immunocompromised mice can further be improved by introducing additional deletion of gene mig-14. The ssaV, mig-14 double mutant was as efficient as ssaV mutant, with respect to host colonization and eliciting Salmonella-specific mucosal sIgA and serum IgG response in wild-type C57BL/6 mice. Interestingly, this double mutant did not show any systemic infection in immunocompromised mice.ConclusionsThis study suggests that ssaV, mig-14 double mutant strain can be effectively used as a potential vaccine candidate even in immunocompromised mice. Such attenuated vaccine strain could possibly used for expression of heterologous antigens and thus for development of a polyvalent vaccine strain.

Highlights

This study proposes a diverse role for mig-14 in the survival of TTSS-2 deficient Salmonella in immunocompromised mice like Nos2−/−, Il-10−/− and CD40L−/− and explores the possible potential of S
Similar experiment was carried out to assess the performance of MT4 in wt C57BL/6 and CD40L−/− mice
Typhimurium strain; it was appreciable that the mig14::aphT single mutant has reduced ability to colonize to systemic sites (Additional file 1: Figure S1 and Additional file 1: Figure S2); this reduced colonization in liver and spleen was not as sharp as in case of C57BL/6 mice infected with ssaV mutant MT5

Summary

Introduction

Development of Salmonella enterica serovar Typhimurium (S. Typhimurium) live attenuated vaccine carrier strain to prevent enteric infections has been a subject of intensive study. Typhimurium have been proposed as an effective live attenuated vaccine strain Many such mutant strains failed to successfully complete the clinical trials as they were suboptimal in delivering effective safety and immunogenicity. Enteric infections represent a major threat to human health worldwide affecting both children and adults in developing and industrialized countries These infections are caused by a number of pathogens including Salmonella, Shigella, Campylobacter species, Aeromonas, Plesio monas, Vibrio, Yersinia entercolitica, E. coli 0157:H7 and Rotavirus. Earlier studies have shown that only a few such mutants have been tested in a pilot study in order to investigate their protection efficacy [27,28,29] When tested, such a few proposed vaccine strains resulted in developing diseases in the hosts of variable immune status [20,30,31,32].

Methods

Results

Conclusion